1. Field of the Invention
This invention includes 17.alpha.-halo silyl ether steroidal 17.beta.-cyanohydrins useful as intermediates in the production of progesterones, 17-hydroxyprogesterones and corticoid pharmaceuticals as well as processes to produce and use the intermediates.
2. Description of the Related Art
Steroidal 17.beta.-cyano-17.alpha.-hydroxy-17-ethers are known, see for example, U.S. Pat. Nos. 4,500,461, 4,548,748 and 4,585,590 which disclose a variety of ethers including the silyl ethers, t-butyldimethyl silyl and TMS (trimethylsilyl). However, those ethers are not operable in the present invention, .alpha.-halo (halo) silyl ethers are known and have been used as precursors to silicon-stabilized nucleophilic carbanions. See particularly, Silicon in Organic Synthesis, E. Colvin, Butterworth, 1981, pp. 21-29, Synthesis 717 (1985), Tetrahedron Letters 25, 4245 (1984) and Journal of Organic Chemistry 48, 2110 (1983).
Mnay examples of intermolecular addition of carbon nucleophiles, such as methyl Grignard, to protected or unprotected cyanohydrins are known. For the unprotected cyanohydrin see Organic reactions, S. M. McElvain, vol IV, p. 264. For examples of addition of TMS protected cyanohydrins see Synthesis 270 (1981), Tetrahedron Letters 24, 4075 (1983) and Tetrahedron Letters 27, 1933 (1986).
This intermolecular reaction has been used to convert protected steroidal 17.beta.-cyanohydrins to pregnanes and corticoid derivatives, see U.S. Pat. Nos. 4,500,461, 4,548,748 and 4,585,590. Similar chemistry is also described in Bull. Chem. Soc. Japan 58, 978 (1985), Japan Kokai No. 57-062296, 57-062298, 57-062299 and 57-0622300 (Derwent Abstracts 82-42275E/21, 82-42277E/21, 82-42278E/21 and 82-42279E/21 respectively), Tetrahedron Letters 2005 (1971) and U.S. Pat. No. 3,697,510.
Deprontonation of .alpha.-halo silanes to afford nucleophiles is also known, see J. Am. Chem. Spc. 99, 4536 (1977), J. Chem. Soc. Chem. Comm. 513 (1977) and 297 (1978) and Tetrahedron 39, 867 (1983).
Silicon-stabilized carbanions are well known in the art, see E. Colvin, Silicon in Organic Synthesis, Butterworths, 1981. p. 21-29 and Synthesis 717 (1985). With regard to the formation of silicon-stabilized carbanion silyl ethers see J. Org. Chem., 48, 2110 (1983) and Tetrahedron Letters 25, 4245 (1984) where chloromethyl silyl ethers are reduced with magnesium to form the carbanion, which is added to a variety of electrophiles, but not nitriles. .alpha.-Lithio silyl carbanions are similarly prepared by reduction with lithium, J. Am. Chem. Soc., 76, 1619 (1954), and the corresponding sodium and potassium derivatives are known, J. Org. Chem. 26, 2604, (1961). With regard to the deportonation of the halomethyl silanes see J. Am. Chem. Soc., 99, 4536 (1977), J. Chem. Soc. Chem. Comm., 513 (1977), J. Chem. Soc. Chem. Comm., 297 (1978) and Tetrahedron 39, 867 (1983) where trimethylchloromethylsilane is deprotonated with sec-butyllithium. Although these latter silicon-stabilized carbanions have been added to a variety of electrophiles they have not been added to a nitrile carbon and have not been used in steroid chemistry.
Intramolecular cyclization incorporating a silyl ether in the ring are know, but are limited to radical cyclization onto carbon-carbon double and triple bonds and not to nitriles, see J. Org. Chem., 49, 2298 (1984), J. Am. Chem. Soc. 107, 500 (1985), Tetrahedron Letters 27, 2255 (1986), M. Koreeda presentation given at the 190th ACS National Meeting in Chicago on Sept. 11, 1985. The difficulty of promoting intramolecular free-radical cyclizations onto a nitrile is described in J. Org. Chem., 50, 5409 (1985). A process for cyclizing .omega.-halogenated nitriles using magnesium or lithium metal is discussed in J. Organometallic Chem. 87, 25 (1975). While that process uses .omega.-halogenated nitriles it is far different than the process of the present invention. The present invention requires an ether linkage, a silicon atom in the cyclizing sidechain and a steroid parent nucleus. Most importantly the .omega.-halogenated nitriles of the prior art (lacking the ether linkage and the silicon atom) once cyclized can not be opened to form the C.sub.17 side chain necessary for the production of corticoids, progesterones of 17-hydroxyprogesterones as can the .alpha.-halo silyl ether (II).
Oxidative cleavage reactions are known to those skilled in the art, see J. Org. Chem., 48, 2120 (1983), Tetrahedron Letters 25, 4245 (1984), J. Organometallic Chem., 269 (1984), Tetrahedron 39, 983 (1983) and Tetrahedron Letters 27, 75 (1986).